Ageing compromises mouse thymus function and remodels epithelial cell differentiation

Jeanette Baran-Gale; Michael D Morgan; Stefano Maio; Fatima Dhalla; Irene Calvo-Asensio; Mary E Deadman; Adam E Handel; Ashley Maynard; Steven Chen; Foad Green; Rene V Sit; Norma F Neff; Spyros Darmanis; Weilun Tan; Andy P May; John C Marioni; Chris P Ponting; Georg A Holländer

doi:10.7554/eLife.56221

Ageing compromises mouse thymus function and remodels epithelial cell differentiation

Jeanette Baran-Gale, Michael D Morgan, Stefano Maio, Fatima Dhalla, Irene Calvo-Asensio, Mary E Deadman, Adam E Handel, Ashley Maynard, Steven Chen, Foad Green, Rene V Sit, Norma F Neff, Spyros Darmanis, Weilun Tan, Andy P May, John C Marioni, Chris P Ponting, Georg A Holländer

Medical Sciences

Research output: Contribution to journal › Article › peer-review

45 Citations (Scopus)

Abstract

Ageing is characterised by cellular senescence, leading to imbalanced tissue
maintenance, cell death and compromised organ function. This is first observed in the thymus, the
primary lymphoid organ that generates and selects T cells. However, the molecular and cellular
mechanisms underpinning these ageing processes remain unclear. Here, we show that mouse
ageing leads to less efficient T cell selection, decreased self-antigen representation and increased T
cell receptor repertoire diversity. Using a combination of single-cell RNA-seq and lineage-tracing,
we find that progenitor cells are the principal targets of ageing, whereas the function of individual
mature thymic epithelial cells is compromised only modestly. Specifically, an early-life precursor cell
population, retained in the mouse cortex postnatally, is virtually extinguished at puberty.
Concomitantly, a medullary precursor cell quiesces, thereby impairing maintenance of the
medullary epithelium. Thus, ageing disrupts thymic progenitor differentiation and impairs the core
immunological functions of the thymus.

Original language	English
Number of pages	27
Journal	eLife
DOIs	https://doi.org/10.7554/eLife.56221
Publication status	Published - 25 Aug 2020

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10.7554/eLife.56221Licence: CC BY

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Baran-Gale, J., Morgan, M. D., Maio, S., Dhalla, F., Calvo-Asensio, I., Deadman, M. E., Handel, A. E., Maynard, A., Chen, S., Green, F., Sit, R. V., Neff, N. F., Darmanis, S., Tan, W., May, A. P., Marioni, J. C., Ponting, C. P., & Holländer, G. A. (2020). Ageing compromises mouse thymus function and remodels epithelial cell differentiation. eLife. https://doi.org/10.7554/eLife.56221

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title = "Ageing compromises mouse thymus function and remodels epithelial cell differentiation",

abstract = "Ageing is characterised by cellular senescence, leading to imbalanced tissuemaintenance, cell death and compromised organ function. This is first observed in the thymus, theprimary lymphoid organ that generates and selects T cells. However, the molecular and cellularmechanisms underpinning these ageing processes remain unclear. Here, we show that mouseageing leads to less efficient T cell selection, decreased self-antigen representation and increased Tcell receptor repertoire diversity. Using a combination of single-cell RNA-seq and lineage-tracing,we find that progenitor cells are the principal targets of ageing, whereas the function of individualmature thymic epithelial cells is compromised only modestly. Specifically, an early-life precursor cellpopulation, retained in the mouse cortex postnatally, is virtually extinguished at puberty.Concomitantly, a medullary precursor cell quiesces, thereby impairing maintenance of themedullary epithelium. Thus, ageing disrupts thymic progenitor differentiation and impairs the coreimmunological functions of the thymus.",

author = "Jeanette Baran-Gale and Morgan, {Michael D} and Stefano Maio and Fatima Dhalla and Irene Calvo-Asensio and Deadman, {Mary E} and Handel, {Adam E} and Ashley Maynard and Steven Chen and Foad Green and Sit, {Rene V} and Neff, {Norma F} and Spyros Darmanis and Weilun Tan and May, {Andy P} and Marioni, {John C} and Ponting, {Chris P} and Holl{\"a}nder, {Georg A}",

note = "Acknowledgements: We gratefully acknowledge the Chan Zuckerberg Biohub for support and for sequencing, and mem- bers of the Tabula Muris Consortium for technical assistance. CPP is funded by the MRC (MC_UU_00007/15). CPP, GH, JB and MDM were supported by the Wellcome Trust (grant 105045/ Z/14/Z). JCM was supported by core funding from the European Molecular Biology Laboratory and from Cancer Research UK (award number 17197). GH and ICA was supported by the Swiss National Science Foundation (grant numbers IZLJZ3_171050 and 310030_184672). AEH was supported by a Clinical Lectureship from the NIHR. FD was supported by the Wellcome Trust [109032/Z/15/Z].",

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T1 - Ageing compromises mouse thymus function and remodels epithelial cell differentiation

AU - Baran-Gale, Jeanette

AU - Morgan, Michael D

AU - Maio, Stefano

AU - Dhalla, Fatima

AU - Calvo-Asensio, Irene

AU - Deadman, Mary E

AU - Handel, Adam E

AU - Maynard, Ashley

AU - Chen, Steven

AU - Green, Foad

AU - Sit, Rene V

AU - Neff, Norma F

AU - Darmanis, Spyros

AU - Tan, Weilun

AU - May, Andy P

AU - Marioni, John C

AU - Ponting, Chris P

AU - Holländer, Georg A

N1 - Acknowledgements: We gratefully acknowledge the Chan Zuckerberg Biohub for support and for sequencing, and mem- bers of the Tabula Muris Consortium for technical assistance. CPP is funded by the MRC (MC_UU_00007/15). CPP, GH, JB and MDM were supported by the Wellcome Trust (grant 105045/ Z/14/Z). JCM was supported by core funding from the European Molecular Biology Laboratory and from Cancer Research UK (award number 17197). GH and ICA was supported by the Swiss National Science Foundation (grant numbers IZLJZ3_171050 and 310030_184672). AEH was supported by a Clinical Lectureship from the NIHR. FD was supported by the Wellcome Trust [109032/Z/15/Z].

PY - 2020/8/25

Y1 - 2020/8/25

N2 - Ageing is characterised by cellular senescence, leading to imbalanced tissuemaintenance, cell death and compromised organ function. This is first observed in the thymus, theprimary lymphoid organ that generates and selects T cells. However, the molecular and cellularmechanisms underpinning these ageing processes remain unclear. Here, we show that mouseageing leads to less efficient T cell selection, decreased self-antigen representation and increased Tcell receptor repertoire diversity. Using a combination of single-cell RNA-seq and lineage-tracing,we find that progenitor cells are the principal targets of ageing, whereas the function of individualmature thymic epithelial cells is compromised only modestly. Specifically, an early-life precursor cellpopulation, retained in the mouse cortex postnatally, is virtually extinguished at puberty.Concomitantly, a medullary precursor cell quiesces, thereby impairing maintenance of themedullary epithelium. Thus, ageing disrupts thymic progenitor differentiation and impairs the coreimmunological functions of the thymus.

AB - Ageing is characterised by cellular senescence, leading to imbalanced tissuemaintenance, cell death and compromised organ function. This is first observed in the thymus, theprimary lymphoid organ that generates and selects T cells. However, the molecular and cellularmechanisms underpinning these ageing processes remain unclear. Here, we show that mouseageing leads to less efficient T cell selection, decreased self-antigen representation and increased Tcell receptor repertoire diversity. Using a combination of single-cell RNA-seq and lineage-tracing,we find that progenitor cells are the principal targets of ageing, whereas the function of individualmature thymic epithelial cells is compromised only modestly. Specifically, an early-life precursor cellpopulation, retained in the mouse cortex postnatally, is virtually extinguished at puberty.Concomitantly, a medullary precursor cell quiesces, thereby impairing maintenance of themedullary epithelium. Thus, ageing disrupts thymic progenitor differentiation and impairs the coreimmunological functions of the thymus.

UR - https://doi.org/10.7554/eLife.56221

U2 - 10.7554/eLife.56221

DO - 10.7554/eLife.56221

M3 - Article

JO - eLife

JF - eLife

SN - 2050-084X

ER -

Ageing compromises mouse thymus function and remodels epithelial cell differentiation

Abstract

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